Despite significant advances in respitratory care and reduction in mortality of patients with respiratory failure, morbidity persists, often resulting from iatrogenic mechanisms. In particular, preterm infants weighing less than 1500 grams experience significant acute and chronic respiratory complications. During this era of increasing multiple births secondary to infertility management, a greater number of very low birth weight and very preterm infants are being born, increasing the number of infants that experience these complications. Further, infants weighing less than 500 grams who survive the initial respiratory syndrome of prematurity, commonly (i.e., about 85% of the infants) experience significant chronic lung disease with neurodevelopmental delay. In this regard, these fragile infants represent an underserved population with respect to existing respiratory therapies. For this reason, alternative means to support pulmonary gas exchange while preserving lung structure and function are required.
To partially address this need, liquid assisted ventilation (“LAV”) with breathable liquids such as perfluorochemical (“PFC”) liquids has been investigated as an alternative respiratory modality. The biomedical application of PFC liquids has already been incorporated in clinical medicine for a number of different organ systems (i.e., intravascular PFC emulsions for volume expansion/oxygen carrying/angiography and intracavitary neat PFC liquid for image contrast enhancement or vitreous liquid replacement). As such, pure medical grade PFC liquids currently exist for LAV purposes.
Simplisitically, LAV utilizes a liquid to replace nitrogen gas as the carrier for oxygen and carbon dioxide. By definition, LAV is pulmonary gas exchange supported by tracheal instillation of a breathable liquid such as a PFC liquid. LAV techniques for the support of respiratory gas exchange include tidal liquid ventilation (“TLV”), PFC lavage, partial liquid ventilation (“PLV”), and aerosolized liquids. LAV techniques differ with respect to methodology as well as the impact of the physiochemical profile of the PFC liquid.
A single pump ventilatory system 10 as shown in FIG. 1 can be used for performing the various LAV techniques. For example, the ventilatory system 10 can be used for TLV. During inspiration, a pump 12 is used to pump a warmed and oxygenated PFC liquid from a liquid reservoir 14 through an inspiratory valve 16 in direction 18. The PFC liquid is pumped into lungs 20. During expiration, the PFC liquid is actively pumped out of the lungs 20 (with passive assistance from the naturally occurring lung recoil) in a direction 22. The PFC liquid is then pumped in a direction 24 through a gas exchange filter 26, and if necessary a conditioner 28, before being pumped back to the liquid reservoir 14. In the gas exchange filter 26, carbon dioxide is scrubbed out of the PFC liquid and oxygen is dissolved into the liquid. Control of the inspiration valve 16 and an expiration valve 17 allows recirculation of the PFC liquid in the system 10, without the liquid being delivered to the lungs 20. This recirculation may be necessary if excess amounts of carbon dioxide or insufficient amounts of oxygen are present in the liquid.
Using the system 10, the TLV process is initiated by instilling PFC liquid into the lung of a patient (which is initially filled with gas) while gently manipulating the thorax to assist removal of resident gas volumes into the delivery system. Because gas is transported in dissolved form, the gas-liquid interface at the alveolar surface is eliminated, there are no audible breathing sounds, and inflation pressures are minimized. There is no free gas in the lung and the liquid volumes in the lung and ventilator are monitored and controlled to maintain effective gas exchange. In this way, substantially all gas-liquid interfacial tension is eliminated and the lung is provided maximal protection from inflation pressures as lung volume is recruited, compliance is increased, and inflation pressures and pulmonary barotraumas are reduced.
The control of the ventilatory system can be achieved by cycling the liquid using a mechanical ventilator, which can include manually controlled flow-assist pneumatic systems, roller pumps with pneumatic/liquid/electronic controls, and gravity driven and modified ExtraCorporeal Membrane Oxygenation (“ECMO”) circuits. Current control strategies include constant pressure or constant flow or time-cycling with pressure (system, airway, or alveolar) and/or volume (lung volume, tidal volume) limitations. The current approaches may provide for a servo-controlled system based on feedback of ventilatory parameters such as those shown in FIG. 2 where values for inspiration period 34 and expiration period 36 are obtained. However, the current approaches do not provide for a delivery system with a microprocessor or servo-control unit that maintains gas exchange, optimizes lung function, minimizes ventilation pressures, and optimally delivers a biological agent to the patient.
In an effort to optimize delivery of breathable liquids in a ventilatory system, Tidal liquid ventilation algorithms that address optimum frequency (3-8 breaths/minute), tidal volume (about 15 ml/kg) and inspiratory:expiratory timing (1:2 or 1:3) have been developed. Those algorithms are run as a control strategy to maintain adequate CO2 elimination (up to 4× steady state values), minimize resistive pressures and expiratory flow limitations associated with moving the relatively more dense and viscous respiratory medium, and overcome diffusional dead space associated with CO2 diffusivity in a liquid respiratory media. The control strategy allows for proximal airway pressures to be rapidly dissipated through the bronchopulmonary tree during TLV such that alveolar pressures are markedly lower than airway pressures. As a result, pulmonary debris (i.e., exudates, meconium, mucous) is readily moved by tidal PFC volumes and cleared by the TLV filtering systems.
The ventilation system shown in FIG. 1 can also be used for partial liquid ventilation (“PLV”). PLV can be performed by filling and maintaining the lung with a functional residual capacity of PFC liquid while mechanical gas ventilation is performed. In this way, PLV is similar to TLV as it utilizes the alveolar recruitment capabilities of a low surface tension liquid to establish an adequate functional residual capacity (i.e., lung volume after a normal expiration) in a surfactant deficient, or impaired lung. The PFC liquid is oxygenated and CO2 is exchanged in the lung through mechanical gas ventilation.
The technical aspect of instilling PFC liquid and adjustment of the gas ventilator are known in the art, but effective ventilation of a lung which is partly filled with liquid and partly filled with gas is more challenging since there are many unknowns with respect to the distribution of PFC liquid in the lung, oxygen and carbon dioxide saturation of resident PFC, continually changing lung mechanics, evaporative loss of PFC, and changing volumes of gas and PFC lung volumes. Thus, there is a need for constant monitoring and adjustment of ventilatory parameters.
Although various LAV techniques are used in treating pulmonary disorders, what is still needed is a method for effectively treating pulmonary disorders with breathable liquids and biological agents. In particular, what is needed is a method for treating pulmonary disorders with breathable liquids and biological agents, wherein the method is practiced using a microprocessor or a servo-control unit to control the delivery system so as to maintain gas exchange, optimize lung function, minimize ventilation pressures, and optimally deliver the biological agents.